Mainolfi, Nello, Powers, James, Meredith, Erik, Elliott, Jason, Poor, Stephen, Liu, Fang and Anderson, Karen (2016) Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG. ACS Medicinal Chemistry Letters, 7 (4). pp. 357-362. ISSN 1948-5875

Abstract

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

Item Type:	Article
Keywords:	AMD bicyclic core KDR scaffold morphing Vascular endothelial growth factor receptor 2 VEGF
Date Deposited:	13 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/21245